Doxycycline hydrochloride preparation and preparation method thereof

Abstract

The invention provides a doxycycline hydrochloride preparation and a preparation method thereof, and belongs to the field of doxycycline hydrochloride preparations. The preparation method comprises the following steps: pretreatment of doxycycline hydrochloride, preparation of a primary preparation, secondary treatment and post-treatment. The doxycycline hydrochloride pretreatment step comprises the following steps: adding doxycycline hydrochloride into 1, 2-propylene glycol, uniformly stirring, adding pretreated succinic anhydride, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS), and reacting for 9-12 hours to obtain pretreated doxycycline hydrochloride; the doxycycline hydrochloride preparation prepared by the invention is good in light resistance in water, stable in slow release performance in animal bodies, capable of realizing long-time continuous stable release and excellent in storage resistance.

Description

Technical Field

[0001] The present invention belongs to the field of doxycycline hydrochloride preparations, and particularly relates to a doxycycline hydrochloride preparation and a preparation method thereof. Background Art

[0002] Doxycycline hydrochloride belongs to tetracycline antibiotics. It is a light yellow or yellow crystalline powder and is a broad-spectrum antibacterial drug. It inhibits protein synthesis by binding to the ribosome of bacteria, thereby exerting antibacterial effects. It is commonly used in veterinary clinics to treat Escherichia coli disease, salmonellosis, pasteurellosis caused by sensitive Gram-positive bacteria and Gram-negative bacteria, and respiratory diseases caused by mycoplasma.

[0003] The structure of doxycycline hydrochloride contains multiple groups that are prone to oxidation or hydrolysis, such as phenolic hydroxyl groups, enol groups, and amide groups. It is unstable to light in water and easily forms isomers, resulting in the discoloration of its solution system. Drinking water administration has the advantages of simple operation, less labor, and the ability to be used in groups, and is gradually widely used in farms. Currently, doxycycline hydrochloride is mainly administered by drinking water. The doxycycline hydrochloride preparation for drinking water administration has problems of easy degradation and poor stability. Moreover, it has a fast metabolism in animals, large fluctuations in blood pressure concentration, and requires multiple administrations per day, resulting in poor compliance in medication and increased breeding costs. In addition, the doxycycline hydrochloride preparation is irritating to the gastrointestinal mucosa of animals and is prone to inducing bacterial drug resistance and weakening the effect when administered multiple times in a short period.

[0004] In order to enhance the stability of doxycycline hydrochloride preparation in water, CN115737656A discloses a doxycycline hydrochloride preparation, a preparation method thereof, and an application. Specifically, it discloses that the doxycycline hydrochloride preparation is prepared from doxycycline hydrochloride, a light-shielding agent, an oxygen barrier agent, and an adsorption carrier. The light-shielding agent is a plant essential oil with ultraviolet absorption effect, and the oxygen barrier agent is an oily substance with antioxidant effect. When administered by centralized drinking water, it can form an upper light-shielding agent system, a middle chicken-raising system, and a lower doxycycline hydrochloride aqueous solution system. The lower doxycycline hydrochloride aqueous solution is protected by the light-shielding layer and the oxygen barrier layer, and its stability is greatly improved, solving the technical problem of easy oxidation, hydrolysis, and light instability of doxycycline hydrochloride during centralized drinking water administration.

[0005] The doxycycline hydrochloride preparation prepared by this method has improved light resistance in water and reduced decomposition rate, but its sustained-release performance is poor.

[0006] CN106031715A discloses a doxycycline hydrochloride sustained-release preparation and a preparation method thereof. The preparation method is to first prepare pellets from doxycycline hydrochloride and auxiliary materials according to a formula, then coat the pellets with a sustained-release material, and finally mix the coated pellets with appropriate external auxiliary materials for tabletting, or directly fill the sustained-release coated pellets into capsules to obtain the doxycycline hydrochloride sustained-release preparation; The dissolution experiment of the doxycycline hydrochloride sustained-release preparation prepared by this method shows that the drug is slowly released in a solution with pH 1.2 (simulating gastric juice) and rapidly released in a solution with pH 5.5 (simulating intestinal juice). This preparation delays the release of the drug in the stomach, and at the same time can ensure the concentrated release and absorption of the drug in the small intestine, which can not only reduce the side effects of the drug, does not affect the rapid onset of the drug, but also improves the bioavailability of the drug and ensures that the drug exerts the maximum therapeutic effect.

[0007] However, for the doxycycline hydrochloride sustained-release preparation prepared by this method, in the simulation test of intestinal juice, the release rate is relatively fast at the initial stage of drug release, and the subsequent release rate is too slow to achieve long-term continuous and stable release.

[0008] Moreover, the doxycycline hydrochloride preparations prepared by the prior art usually have problems of high moisture absorption rate and easy moisture absorption and caking. Summary of the Invention

[0009] In order to solve the technical problems existing in the prior art, the present invention provides a doxycycline hydrochloride preparation and a preparation method thereof. The doxycycline hydrochloride preparation has good light resistance in water, and has stable sustained-release performance in animals, can achieve long-term continuous and stable release, and has excellent storage resistance.

[0010] In view of the above technical problems, the present invention adopts the following technical solutions: A preparation method of a doxycycline hydrochloride preparation, including doxycycline hydrochloride pretreatment, primary preparation, secondary treatment and post-treatment steps, specifically as follows: 1. Doxycycline hydrochloride pretreatment Add polyethylene glycol 2000 to 1,2-propanediol, raise the temperature to 56 - 60 °C, stir for 26 - 35 min, then add succinic anhydride, stir for 18 - 23 min, and then add triethylamine. Keep stirring under a nitrogen atmosphere for 3.8 - 4.2 h, and obtain pretreated succinic anhydride after filtration, washing and drying; The mass ratio of the 1,2-propanediol, polyethylene glycol 2000, succinic anhydride and triethylamine is 100:8.2 - 8.7:1.5 - 2.0:0.3 - 0.5; Add doxycycline hydrochloride to 1,2 - propanediol. After stirring evenly, add pretreated succinic anhydride. After stirring evenly, add 1 - ethyl - 3 - (3 - dimethylaminopropyl) carbodiimide hydrochloride (EDC) and N - hydroxysuccinimide (NHS), and stir and react for 9 - 12 h. After washing and drying, pretreated doxycycline hydrochloride is obtained. The mass ratio of the 1,2 - propanediol, doxycycline hydrochloride, pretreated succinic anhydride, 1 - ethyl - 3 - (3 - dimethylaminopropyl) carbodiimide hydrochloride (EDC), and N - hydroxysuccinimide (NHS) is 100:4.0 - 4.5:7.0 - 7.4:0.8 - 1.0:0.40 - 0.50.

[0011] 2. Prepare the primary preparation Add glycidyl methacrylate to 1,2 - propanediol, and stir at 240 - 260 rpm for 32 - 37 min to obtain a glycidyl methacrylate solution; add polyvinylpyrrolidone and poloxamer 407 to 1,2 - propanediol, stir for 28 - 32 min, add triethylamine, stir evenly, then add the glycidyl methacrylate solution, control the addition rate at 0.8 - 1.2 g / min, and control the stirring speed at 140 - 160 rpm while adding. After adding, raise the temperature to 50 - 54 °C and keep warm and react for 5.2 - 5.6 h under a nitrogen atmosphere. After the reaction ends, through separation, washing and drying, the primary coating agent is obtained. The mass ratio of the glycidyl methacrylate and 1,2 - propanediol is 4.5 - 5.3:95. The mass ratio of the 1,2 - propanediol, polyvinylpyrrolidone, poloxamer 407, triethylamine, and glycidyl methacrylate solution is 300:6.0 - 6.4:3.6 - 4.0:0.30 - 0.35:34 - 37. Put the pretreated doxycycline hydrochloride into 1,2 - propanediol, stir evenly to obtain a pretreated doxycycline hydrochloride solution; put the primary coating agent into 1,2 - propanediol, stir evenly, then raise the temperature to 34 - 38 °C, add the pretreated doxycycline hydrochloride solution, control the addition rate at 1.8 - 2.3 g / min. After adding, add triethylamine again, raise the temperature at a rate of 0.4 - 0.6 °C / min to 54 - 58 °C, keep warm and stir for 3.8 - 4.2 h. After the heat preservation ends, through separation, washing and drying, the primary preparation is obtained. The mass ratio of the pretreated doxycycline hydrochloride and 1,2 - propanediol is 8.2 - 8.8:100. The mass ratio of the primary coating agent, 1,2 - propanediol, pretreated doxycycline hydrochloride solution, and triethylamine is 3.0 - 3.5:100:115 - 124:0.12 - 0.17.

[0012] 3. Secondary treatment Add the modified chitosan into the acetic acid solution, stir evenly, then add the primary preparation, raise the temperature to 52 - 57 °C, stir at 200 - 230 rpm for 1.8 - 2.2 h. After stirring, lower the temperature to 34 - 38 °C, add protocatechuic aldehyde, keep the temperature and stir for 1.8 - 2.2 h, then filter, wash and dry to obtain the secondary preparation; The mass ratio of the modified chitosan, acetic acid solution, primary preparation, and protocatechuic aldehyde is 2.0 - 2.5:240 - 260:7.3 - 7.8:1.6 - 1.8; The mass concentration of the acetic acid solution is 4.8 - 5.2%; The preparation method of the modified chitosan is as follows: Put the chitosan into deionized water, stir evenly, then add dodecyl glycidyl ether, raise the temperature to 56 - 60 °C, stir and react for 2.4 - 2.6 h, then lower the temperature to 43 - 47 °C, add polyethylene glycol diglycidyl ether, keep the temperature and stir for 2.3 - 2.7 h. After stirring, filter, wash and dry to obtain the modified chitosan; The mass ratio of the chitosan, deionized water, dodecyl glycidyl ether, and polyethylene glycol diglycidyl ether is 4.7 - 5.2:100:0.7 - 1.0:1.4 - 1.6.

[0013] 4. Post - treatment Add the secondary preparation into deionized water, stir evenly, then add Tween 80, polyvinyl alcohol, and anhydrous glucose. After mixing evenly, add hypromellose, stir evenly, then granulate and dry to obtain the doxycycline hydrochloride preparation The mass ratio of the secondary preparation, deionized water, Tween 80, polyvinyl alcohol, anhydrous glucose, and hypromellose is 28 - 32:30 - 34:2.3 - 2.6:1.5 - 1.8:13 - 16:5.5 - 5.8.

[0014] A doxycycline hydrochloride preparation is prepared by the aforementioned preparation method.

[0015] The present invention prepares a doxycycline hydrochloride preparation. First, doxycycline hydrochloride is pretreated. Specifically, polyethylene glycol reacts with succinic anhydride to form an ester bond, increasing the molecular weight and polarity of succinic anhydride, enhancing the hydrophilicity of the pretreated succinic anhydride, which is beneficial to the dispersion and sustained release of the product. Then, through an amidation reaction, the pretreated succinic anhydride is combined with doxycycline hydrochloride, increasing the hydrophilicity of the product and its dispersibility in water, achieving the sustained release performance of the product, and reducing the exposure of groups in the doxycycline hydrochloride molecule that are prone to oxidation and hydrolysis, improving the stability of the preparation; in the step of preparing the primary preparation, first, glycidyl methacrylate undergoes a ring-opening reaction with polyvinylpyrrolidone and poloxamer to obtain a three-dimensional polymer network, which coats the pretreated doxycycline hydrochloride, improving the biocompatibility of the primary preparation, and further enhancing the uniformity and sustained release stability of the product; in the secondary treatment step, first, dodecyl glycidyl ether is introduced to treat chitosan to introduce long-chain hydrophobic groups, reducing the hygroscopicity of the product during storage. Then, polyethylene glycol diglycidyl ether is introduced to enhance hydrophilicity, achieving the regulation and balance of hydrophilicity and hydrophobicity. Then, it is mixed with the primary preparation. The aldehyde group of protocatechuic aldehyde and the amino group of chitosan can crosslink to form a stable crosslinked network, and chitosan has good binding properties and strong interaction with groups such as epoxy groups and hydroxyl groups in the primary preparation, and has good biocompatibility with the primary preparation. Combining the post-treatment steps, the stability of doxycycline hydrochloride is achieved, reducing its degradation in water, improving the sustained release stability in animals, and reducing the hygroscopicity during storage, improving the storage stability.

[0016] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0017] 1. The doxycycline hydrochloride prepared by the present invention is formulated into a solution with a doxycycline hydrochloride concentration of 2100 mg / L. When irradiated under room temperature and an illumination of 5000 lux, the decomposition rate after 6.0 h of irradiation is 1.2 - 1.5%, and the decomposition rate after 12.0 h of irradiation is 2.5 - 2.8%; 2. The doxycycline hydrochloride prepared by the present invention undergoes a digestion test in gastric juice. The release rate at the 1st h is 2.3 - 2.9%, and the release rate at the 2nd h is 3.5 - 4.5%; When undergoing a digestion test in intestinal juice, the release rate at the 2nd h is 10.2 - 12.4%, the release rate at the 6th h is 26.2 - 28.6%, the release rate at the 8th h is 45.9 - 49.7%, the release rate at the 12th h is 67.8 - 70.2%, and the release rate at the 24th h is 98.4 - 99.2%; 3. The doxycycline hydrochloride prepared by the present invention is placed in an environment with a temperature of 60 °C and a humidity of 80% and left standing for 10 d, and the weight change rate is 1.5 - 1.8%. Detailed implementation manners

[0018] To clearly understand the technical features, objectives, and effects of the present invention, the specific embodiments of the present invention will now be described.

[0019] Example 1

[0020] 1. Pretreatment of doxycycline hydrochloride 8.7 g of polyethylene glycol 2000 was added to 100 g of 1,2 - propanediol, and the temperature was raised to 60 °C. After stirring for 35 min, 2.0 g of succinic anhydride was added, and stirring was continued for 23 min. Then, 0.5 g of triethylamine was added, and the mixture was kept stirring under a nitrogen atmosphere for 4.2 h. After filtration, washing, and drying, the pretreated succinic anhydride was obtained. 4.5 g of doxycycline hydrochloride was added to 100 g of 1,2 - propanediol, and after stirring evenly, 7.4 g of the pretreated succinic anhydride was added. After stirring evenly, 1.0 g of 1 - ethyl - 3 - (3 - dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 0.50 g of N - hydroxysuccinimide (NHS) were added, and the mixture was stirred and reacted for 9 h. After washing and drying, the pretreated doxycycline hydrochloride was obtained.

[0021] 2. Preparation of the primary preparation 5.3 g of glycidyl methacrylate was added to 95 g of 1,2 - propanediol, and the mixture was stirred at 260 rpm for 37 min to obtain a glycidyl methacrylate solution. 6.4 g of polyvinylpyrrolidone and 4.0 g of poloxamer 407 were added to 300 g of 1,2 - propanediol, and after stirring for 32 min, 0.35 g of triethylamine was added. After stirring evenly, 37 g of the glycidyl methacrylate solution was added, and the addition rate was controlled at 1.2 g / min. While adding, the stirring speed was controlled at 160 rpm. After the addition was completed, the temperature was raised to 54 °C, and the mixture was kept reacting under a nitrogen atmosphere for 5.6 h. After the reaction ended, through separation, washing, and drying, the primary coating agent was obtained. 8.8 g of the pretreated doxycycline hydrochloride was put into 100 g of 1,2 - propanediol, and after stirring evenly, a pretreated doxycycline hydrochloride solution was obtained. 3.5 g of the primary coating agent was put into 100 g of 1,2 - propanediol, and after stirring evenly, the temperature was raised to 38 °C. 124 g of the pretreated doxycycline hydrochloride solution was added, and the addition rate was controlled at 2.3 g / min. After the addition was completed, 0.17 g of triethylamine was added, and the temperature was raised to 58 °C at a rate of 0.6 °C / min, and the mixture was kept stirring for 4.2 h. After the heat preservation ended, through separation, washing, and drying, the primary preparation was obtained.

[0022] 3. Secondary treatment Add 2.5 g of modified chitosan to 260 g of 5.2 wt% acetic acid solution. After stirring evenly, add 7.8 g of primary preparation. Raise the temperature to 57 °C and stir for 1.8 h at 230 rpm. After the stirring is completed, lower the temperature to 38 °C, add 1.8 g of protocatechuic aldehyde, keep the temperature and stir for 1.8 h. After filtration, washing and drying, the secondary preparation is obtained. The preparation method of the modified chitosan is as follows: Put 5.2 g of chitosan into 100 g of deionized water. After stirring evenly, add 1.0 g of dodecyl glycidyl ether. Raise the temperature to 60 °C and stir and react for 2.6 h. Then lower the temperature to 47 °C, add 1.6 g of polyethylene glycol diglycidyl ether, keep the temperature and stir for 2.7 h. After the stirring is completed, after filtration, washing and drying, the modified chitosan is obtained.

[0023] 4. Post-treatment Add 32 g of secondary preparation to 34 g of deionized water. After stirring evenly, add 2.6 g of Tween 80, 1.8 g of polyvinyl alcohol, and 16 g of anhydrous glucose. After mixing evenly, add 5.8 g of hypromellose. After stirring evenly, granulate and dry to obtain the doxycycline hydrochloride preparation.

[0024] Example 2

[0025] 1. Pretreatment of doxycycline hydrochloride Add 8.5 g of polyethylene glycol 2000 to 100 g of 1,2-propanediol. Raise the temperature to 58 °C and stir for 30 min. Then add 1.7 g of succinic anhydride and stir for 20 min. Then add 0.4 g of triethylamine and keep stirring under nitrogen atmosphere for 4.0 h. After filtration, washing and drying, the pretreated succinic anhydride is obtained. Add 4.3 g of doxycycline hydrochloride to 100 g of 1,2-propanediol. After stirring evenly, add 7.2 g of pretreated succinic anhydride. After stirring evenly, add 0.9 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 0.45 g of N-hydroxysuccinimide (NHS), and stir and react for 10 h. After washing and drying, the pretreated doxycycline hydrochloride is obtained.

[0026] 2. Preparation of primary preparation 5.0 g of glycidyl methacrylate was added to 95 g of 1,2 - propanediol, and stirred at 250 rpm for 35 min to obtain a glycidyl methacrylate solution; 6.2 g of polyvinylpyrrolidone and 3.8 g of poloxamer 407 were added to 300 g of 1,2 - propanediol, stirred for 30 min, 0.32 g of triethylamine was added, and after stirring evenly, 36 g of the glycidyl methacrylate solution was added, controlling the addition rate at 1.0 g / min, and while adding, controlling the stirring speed at 150 rpm. After the addition was completed, the temperature was raised to 52 °C, and the reaction was carried out under a nitrogen atmosphere for 5.4 h. After the reaction was completed, through separation, washing and drying, a primary coating agent was obtained; 8.5 g of pretreated doxycycline hydrochloride was put into 100 g of 1,2 - propanediol, and after stirring evenly, a pretreated doxycycline hydrochloride solution was obtained; 3.2 g of the primary coating agent was put into 100 g of 1,2 - propanediol, and after stirring evenly, the temperature was raised to 36 °C, 120 g of the pretreated doxycycline hydrochloride solution was added, controlling the addition rate at 2.0 g / min. After the addition was completed, 0.15 g of triethylamine was added, and the temperature was raised to 56 °C at a rate of 0.5 °C / min, and stirred for 4.0 h. After the heat preservation was completed, through separation, washing and drying, a primary preparation was obtained.

[0027] 3. Secondary treatment 2.3 g of modified chitosan was added to 250 g of 5.0 wt% acetic acid solution, and after stirring evenly, 7.5 g of the primary preparation was added. The temperature was raised to 55 °C, and stirred at 220 rpm for 2.0 h. After the stirring was completed, the temperature was lowered to 36 °C, 1.7 g of protocatechuic aldehyde was added, and stirred for 2.0 h. After filtration, washing and drying, a secondary preparation was obtained; The preparation method of the modified chitosan was as follows: 5.0 g of chitosan was put into 100 g of deionized water, and after stirring evenly, 0.8 g of dodecyl glycidyl ether was added. The temperature was raised to 58 °C and stirred for 2.5 h. Then the temperature was lowered to 45 °C, 1.5 g of polyethylene glycol diglycidyl ether was added, and stirred for 2.5 h. After the stirring was completed, through filtration, washing and drying, the modified chitosan was obtained.

[0028] 4. Post - treatment 30 g of the secondary preparation was added to 32 g of deionized water, and after stirring evenly, 2.5 g of Tween 80, 1.7 g of polyvinyl alcohol, and 15 g of anhydrous glucose were added. After mixing evenly, 5.7 g of hypromellose was added, and after stirring evenly, through granulation and drying, a doxycycline hydrochloride preparation was obtained.

[0029] Example 3

[0030] 1. Pretreatment of doxycycline hydrochloride 8.2 g of polyethylene glycol 2000 was added to 100 g of 1,2 - propanediol. The temperature was raised to 56 °C and stirred for 26 min. Then 1.5 g of succinic anhydride was added and stirred for 18 min. Subsequently, 0.3 g of triethylamine was added, and the mixture was stirred under a nitrogen atmosphere for 3.8 h. After filtration, washing, and drying, pretreated succinic anhydride was obtained. 4.0 g of doxycycline hydrochloride was added to 100 g of 1,2 - propanediol and stirred evenly. Then 7.0 g of pretreated succinic anhydride was added and stirred evenly. Next, 0.8 g of 1 - ethyl - 3 - (3 - dimethylaminopropyl)carbodiimide hydrochloride (EDC) and 0.40 g of N - hydroxysuccinimide (NHS) were added, and the mixture was stirred and reacted for 12 h. After washing and drying, pretreated doxycycline hydrochloride was obtained.

[0031] 2. Preparation of primary preparation 4.5 g of glycerol methacrylate was added to 95 g of 1,2 - propanediol and stirred at 240 rpm for 32 min to obtain a glycidyl methacrylate solution. 6.0 g of polyvinylpyrrolidone and 3.6 g of poloxamer 407 were added to 300 g of 1,2 - propanediol and stirred for 28 min. Then 0.30 g of triethylamine was added and stirred evenly. Subsequently, 34 g of the glycidyl methacrylate solution was added while controlling the addition rate at 0.8 g / min and the stirring speed at 140 rpm during the addition. After the addition was completed, the temperature was raised to 50 °C and the mixture was reacted under a nitrogen atmosphere for 5.2 h. After the reaction ended, through separation, washing, and drying, a primary coating agent was obtained. 8.2 g of pretreated doxycycline hydrochloride was put into 100 g of 1,2 - propanediol and stirred evenly to obtain a pretreated doxycycline hydrochloride solution. 3.0 g of the primary coating agent was put into 100 g of 1,2 - propanediol and stirred evenly. Then the temperature was raised to 34 °C, and 115 g of the pretreated doxycycline hydrochloride solution was added while controlling the addition rate at 1.8 g / min. After the addition was completed, 0.12 g of triethylamine was added, and the temperature was raised to 54 °C at a rate of 0.4 °C / min and stirred for 3.8 h. After the heat preservation ended, through separation, washing, and drying, a primary preparation was obtained.

[0032] 3. Secondary treatment 2.0 g of modified chitosan was added to 240 g of 4.8 wt% acetic acid solution and stirred evenly. Then 7.3 g of the primary preparation was added, and the temperature was raised to 52 °C and stirred at 200 rpm for 2.2 h. After the stirring ended, the temperature was lowered to 34 °C, 1.6 g of protocatechuic aldehyde was added, and the mixture was stirred and heated for 2.2 h. After filtration, washing, and drying, a secondary preparation was obtained. The preparation method of the modified chitosan is as follows: 4.7 g of chitosan is put into 100 g of deionized water. After stirring evenly, 0.7 g of dodecyl glycidyl ether is added. The temperature is raised to 56 °C and stirred for reaction for 2.4 h. Then the temperature is lowered to 43 °C, 1.4 g of polyethylene glycol diglycidyl ether is added, and it is stirred for 2.3 h under insulation. After the stirring is completed, it is filtered, washed, and dried to obtain the modified chitosan.

[0033] 4. Post-treatment 28 g of the secondary preparation is added to 30 g of deionized water. After stirring evenly, 2.3 g of Tween 80, 1.5 g of polyvinyl alcohol, and 13 g of anhydrous glucose are added. After mixing evenly, 5.5 g of hypromellose is added. After stirring evenly, it is granulated and dried to obtain the doxycycline hydrochloride preparation.

[0034] Comparative Example 2-1 Based on Example 2, the changes are as follows: (1) The pretreatment step of doxycycline hydrochloride is omitted. In the primary preparation step, the pretreated doxycycline hydrochloride is replaced with doxycycline hydrochloride without any treatment in equal amount; (2) In the secondary treatment step, the modified chitosan is replaced with chitosan components without any treatment in equal amount; The remaining operations are the same.

[0035] Comparative Example 2-2 Based on Example 2, the changes are as follows: In the primary preparation step of the primary preparation, the primary coating agent is prepared by mixing 6.2 g of polyvinylpyrrolidone and 3.8 g of poloxamer 407 evenly; The remaining operations are the same.

[0036] Performance test The doxycycline hydrochloride preparations prepared in Examples 1-3, Comparative Example 2-1, and Comparative Example 2-2 are subjected to performance tests as follows: 1. Light decomposition rate The doxycycline hydrochloride preparations prepared in Examples 1-3, Comparative Example 2-1, and Comparative Example 2-2 are added to deionized water to prepare a solution with a doxycycline hydrochloride concentration of 2100 mg / L, and then placed at room temperature for light exposure. The light exposure conditions are controlled at 5000 lux. At different times of light exposure, the content of doxycycline hydrochloride in the doxycycline hydrochloride solution is detected, and the light decomposition rate % of the doxycycline hydrochloride preparation is calculated. The calculation results are as follows:

[0037] 2. Sustained-release performance (1) Release in gastric juice Put 1.0 g of the doxycycline hydrochloride preparations prepared in Examples 1 - 3, Comparative Example 2 - 1, and Comparative Example 2 - 2 into 1000 mL of simulated gastric fluid, stir at 100 rpm and 37 °C for 2.0 h to obtain digested gastric fluid, and test the cumulative release rate (%) at different times; among them, the preparation method of the simulated gastric fluid is to add 1.0 mol / L hydrochloric acid solution to 100 mL of deionized water to adjust the pH to 1.2, and then add 0.30 g of pepsin and stir evenly to obtain the simulated gastric fluid; the test results are as follows:

[0038] (2)Release in intestinal fluid Add 1.0 wt% sodium hydroxide solution to the digested gastric fluid obtained after digestion of the doxycycline hydrochloride preparations prepared in Examples 1 - 3, Comparative Example 2 - 1, and Comparative Example 2 - 2 in simulated gastric fluid, adjust the pH to 6.8, and stir at 100 rpm and 37 °C for 12.0 h. Record the cumulative release rate (%) at different times, and the recording results are as follows:

[0039] 3. Hygroscopicity Dry the doxycycline hydrochloride preparations prepared in Examples 1 - 3, Comparative Example 2 - 1, and Comparative Example 2 - 2 at 60 °C for 24 h to obtain test specimens. Place 20 g of the test specimens in an environment with a temperature of 60 °C and a humidity of 80% and let them stand for 10 d. After the standing is over, test their weights again and calculate the weight change rate (%). The results are as follows:

[0040] The present invention prepares a doxycycline hydrochloride preparation. First, doxycycline hydrochloride is pretreated. Specifically, polyethylene glycol reacts with succinic anhydride to form an ester bond, increasing the molecular weight and polarity of succinic anhydride, enhancing the hydrophilicity of the pretreated succinic anhydride, which is beneficial to the dispersion and sustained release of the product. Then, through amidation reaction, the pretreated succinic anhydride is combined with doxycycline hydrochloride, increasing the hydrophilicity of the product and its dispersibility in water, achieving the sustained release performance of the product, and reducing the exposure of the groups in the doxycycline hydrochloride molecule that are prone to oxidation and hydrolysis, improving the stability of the preparation; in the step of preparing the primary preparation, first, glycidyl methacrylate undergoes a ring-opening reaction with polyvinylpyrrolidone and poloxamer to obtain a three-dimensional polymer network, which coats the pretreated doxycycline hydrochloride, improving the biocompatibility of the primary preparation, and further enhancing the uniformity and sustained release stability of the product; in the secondary treatment step, first, dodecyl glycidyl ether is introduced to treat chitosan to introduce long-chain hydrophobic groups, reducing the hygroscopicity of the product during storage, then polyethylene glycol diglycidyl ether is introduced to enhance hydrophilicity, achieving the adjustment and balance of hydrophilicity and hydrophobicity, and then it is mixed with the primary preparation. The aldehyde group of protocatechuic aldehyde can crosslink with the amino group of chitosan to obtain a stable crosslinked network, and chitosan has good binding properties and strong interaction with groups such as epoxy groups and hydroxyl groups in the primary preparation, and has good biocompatibility with the primary preparation. Combining with the post-treatment step, the stability of doxycycline hydrochloride is achieved, its degradation in water is reduced, the sustained release stability in animals is improved, the hygroscopicity during storage is reduced, and the storage stability is enhanced.

[0041] In Comparative Example 2-1, the pretreatment step for doxycycline hydrochloride was omitted. It directly used a primary coating agent to treat doxycycline hydrochloride without any treatment. Its binding force with the primary coating agent was poor, the coating was uneven, and the modification treatment of chitosan was also omitted, which would lead to unstable product structure, poor light resistance, premature release in the stomach, and a relatively fast and unstable release rate in intestinal fluid, and would also increase the hygroscopicity rate during storage, reducing the storage resistance. In Comparative Example 2-2, in the step of preparing the primary preparation, only polyvinylpyrrolidone and poloxamer were used as the primary coating agent. The coating structure was unstable, resulting in a high light decomposition rate of the product, low strength of the preparation, easy destruction in gastric juice and intestinal fluid, leading to a relatively fast release rate, poor physical stability, high hygroscopicity rate in a humid environment, and easy caking.

[0042] Unless otherwise specified, the ratios described in the present invention are all mass ratios, and the percentages are all mass percentages.

[0043] Finally, it should be noted that the above are only preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A preparation method of a doxycycline hydrochloride preparation, characterized in that, It includes the steps of doxycycline hydrochloride pretreatment, primary preparation, secondary treatment and post-treatment; The doxycycline hydrochloride pretreatment step is to add doxycycline hydrochloride to 1,2-propanediol, stir evenly, then add pretreated succinic anhydride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and N-hydroxysuccinimide, and react for 9-12 h to obtain pretreated doxycycline hydrochloride; The primary preparation step is to put the primary coating agent into 1,2-propanediol, stir evenly, heat up to 34-38 °C, add the pretreated doxycycline hydrochloride solution and triethylamine, heat up to 54-58 °C, and stir for 3.8-4.2 h to obtain the primary preparation; The preparation method of the primary coating agent is to add polyvinylpyrrolidone and poloxamer 407 to 1,2-propanediol, stir evenly, add triethylamine, then add glycidyl methacrylate solution, heat up to 50-54 °C, and react for 5.2-5.6 h under a nitrogen atmosphere to obtain the primary coating agent; The secondary treatment step is to add modified chitosan to acetic acid solution, stir evenly, add the primary preparation, stir at 52-57 °C and 200-230 rpm for 1.8-2.2 h, cool down to 34-38 °C, add protocatechuic aldehyde, and stir for 1.8-2.2 h to obtain the secondary preparation.

2. The preparation method of a doxycycline hydrochloride preparation according to claim 1, wherein In the doxycycline hydrochloride pretreatment step, the mass ratio of 1,2-propanediol, doxycycline hydrochloride, pretreated succinic anhydride, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and N-hydroxysuccinimide is 100:4.0-4.5:7.0-7.4:0.8-1.0:0.40-0.

50.

3. The preparation method of a doxycycline hydrochloride preparation according to claim 1, wherein In the doxycycline hydrochloride pretreatment step, the preparation method of the pretreated succinic anhydride is to add polyethylene glycol 2000 to 1,2-propanediol, raise the temperature to 56-60 °C, stir for 26-35 min, then add succinic anhydride, stir for 18-23 min, then add triethylamine, and keep stirring under a nitrogen atmosphere for 3.8-4.2 h. After filtration, washing and drying, the pretreated succinic anhydride is obtained; The mass ratio of 1,2-propanediol, polyethylene glycol 2000, succinic anhydride and triethylamine is 100:8.2-8.7:1.5-2.0:0.3-0.

5.

4. The preparation method of a doxycycline hydrochloride preparation according to claim 1, wherein In the primary preparation step, the mass ratio of the primary coating agent, 1,2-propanediol, the pretreated doxycycline hydrochloride solution, and triethylamine is 3.0-3.5:100:115-124:0.12-0.17; The preparation method of the pretreated doxycycline hydrochloride solution is to put the pretreated doxycycline hydrochloride into 1,2-propanediol, stir evenly to obtain the pretreated doxycycline hydrochloride solution; The mass ratio of the pre-treated doxycycline hydrochloride to 1,2-propanediol is 8.2 - 8.8:

100.

5. The preparation method of a doxycycline hydrochloride preparation according to claim 1, characterized in that In the preparation method of the primary coating agent, the mass ratio of 1,2-propanediol, polyvinylpyrrolidone, poloxamer 407, triethylamine, and glycidyl methacrylate solution is 300:6.0 - 6.4:3.6 - 4.0:0.30 - 0.35:34 - 37; The preparation method of the glycidyl methacrylate solution is to add glycidyl methacrylate to 1,2-propanediol and stir at 240 - 260 rpm for 32 - 37 min to obtain the glycidyl methacrylate solution; The mass ratio of glycidyl methacrylate to 1,2-propanediol is 4.5 - 5.3:

95.

6. The preparation method of a doxycycline hydrochloride preparation according to claim 1, characterized in that In the secondary treatment step, the mass ratio of the modified chitosan, acetic acid solution, primary preparation, and protocatechuic aldehyde is 2.0 - 2.5:240 - 260:7.3 - 7.8:1.6 - 1.8; The mass concentration of the acetic acid solution is 4.8 - 5.2%.

7. The preparation method of a doxycycline hydrochloride preparation according to claim 1, characterized in that The preparation method of the modified chitosan is to put chitosan into deionized water, stir evenly, add dodecyl glycidyl ether, raise the temperature to 56 - 60 °C, stir and react for 2.4 - 2.6 h, then lower the temperature to 43 - 47 °C, add polyethylene glycol diglycidyl ether, keep stirring for 2.3 - 2.7 h, after stirring ends, filter, wash, and dry to obtain the modified chitosan; The mass ratio of chitosan, deionized water, dodecyl glycidyl ether, and polyethylene glycol diglycidyl ether is 4.7 - 5.2:100:0.7 - 1.0:1.4 - 1.

6.

8. The preparation method of a doxycycline hydrochloride preparation according to claim 1, characterized in that The post-treatment step is to add the secondary preparation to deionized water, stir evenly, add Tween 80, polyvinyl alcohol, and anhydrous glucose, mix evenly, add hypromellose, stir evenly, and then granulate and dry to obtain the doxycycline hydrochloride preparation The mass ratio of the secondary preparation, deionized water, Tween 80, polyvinyl alcohol, anhydrous glucose, and hypromellose is 28 - 32:30 - 34:2.3 - 2.6:1.5 - 1.8:13 - 16:5.5 - 5.

8.

9. A doxycycline hydrochloride preparation prepared by the preparation method according to any one of claims 1 - 8.

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